Production of 17beta-alkyl ethers of 16-keto-17beta-hydroxy steroids



United States Patent ()fltice 3,067,215 Patented Dec. 4, 1962 PRODUCTION 9F 17BETA-ALKYL ETHERS F 16- KETO-IIBETA-HYDROXY STERUIDS Max N. Huffman, Colorado Springs, Colo., assignor to Lasdon Foundation, Inc, Yonkers, N.Y., a corporation of Delaware No Drawing. Filed May 9, 1960, Ser. No. 27,962 8 Claims. (Cl. 26tl--397.4)

where R is an alkyl radical, from 16-keto-l7beta-hydroxy steroids wherein the D ring has the formula by reaction with an alkyl ester in the presence of alkali.

This application is a continuation-in-part of my copending application Serial No. 728,210, filed April 14, 1958, now Patent No. 2,945,048, granted July 12,- 1960.

The alkylation of phenolic hydroxyl radicals in steroids and related compounds by reaction with dialkyl sulfates and aqueous alkali is well known. However, the production of alkyl ethers of steroids containing hydroxyl radicals on rings which are not aromatic is a different problem from the alkylation of phenolic materials. In light of this knowledge it was surprising to discover that the l7beta-hydroxyl radical of a steroid containing a keto or oxo substituent in the l6-position can be etherified by reaction with a dialkyl sulfate in the presence of alkali.

This procedure is applicable to all steroids whether fully saturated or having one or more aromatic rings or having intermediate stages of unsaturation. In short, the reaction is applicable to cyclopentanopolyhydrophenam threne compounds wherein thecyclopentano ring has the following structure:

In accordance with this invention the cyclopentanopolyhydrophenanthrene compound having a 16-keto substituent and a l-7bet'a-hydroxyl radical is dissolved in a water-miscible organic solvent. Preferably a stoichiometric excess of aqueous alkali is initially added to the solution, although this step is optional. Thereafter a dialkyl sulfate, such as dimethyl sulfate, and an aqueous alkali solutionare introduced simultaneously into the reaction mixture pro rata, until substantial excesses of both reagents are present. The reaction mixture of cyclopentanopolyhydrophenanthrene compound and dialkyl sulfate in organic solvent is maintained on the alkaline side throughout the operation, that is, at a pH value in the range of 8 to 14. The reaction mixture is agitated and heated at a temperature in the range of 50 to C. for a period of time ranging from hour to 3 or more hours. It is important during the reaction that the dialkyl sulfate and the alkali be added at substantially the same rate so that approximately stoichiometric quantities of each reagent are introduced in the same period of time. However, it is not necessary that this rate be absolutely equal for each reagent because reasonable excesses of one reagent do not adversely aifect the reaction. The alkyl ether of the 16-keto-17beta-hydroxycyclopentanopolyhydrophenanthrene compound can be removed from the reaction mixture by conventional procedures, such as by precipitation by the addition of water or by evaporation of the organic solvent.

In the present invention the dialkyl sulfate can be dimethyl sulfate, diethyl sulfate or similar dialkyl esters of sulfuric acid wherein the alkyl radicals contain 1 to 5 carbon atoms. The alkali is preferably caustic alkali, such as lithium hydroxide, potassium hydroxide or sodium hydroxide. The organic solvents in which the reaction is conveniently conducted are methanol, ethanol, propanol, isopropanol, acetone, methyl ethyl ketone, dioxane and similar water-miscible organic solvents. These solvents may be used in anhydrous form or diluted with water. The reaction is ordinarily conducted by refluxing the reaction mixture and consequently solvents boiling in the range of 50 to 150 C. are preferred.

Steroids to which the etherificati-on procedure is applicable include cyclopentanopolyhydrophenanthrene compounds having a keto (0x0) substituent in the 16-position and a beta-hydroxyl radical in the l7-position. Rings A, B and C of the cyclopentanopolyhydrophenanthrene nucleus may be saturated or unsaturated and the unsaturated rings may be aromatic or only partially unsaturated. For example, the cyclopentanopolyhydrophenanthrene nucleus may be devoid of double bonds as in androstan- 3beta,l7beta-diol-16-one, it may be partially unsaturated as in 5-androsten-Bbeta-methoxy-17beta-ol-16-one or it may contain one or more aromatic rings as in 1,3,5 (10)- estratrien-3,l7beta-ol-16-one.

The invention is further illustrated by the following examples which are representative of procedures Within the scope of this invention. It will be readily understood by those skilled in the art that modifications in conditions and equivalent materials may be made without departing from the invention as described herein.

EXAMPLE 1 3 betw,1 7beta-dimethoacy-5 -andr0sten-1 6 -0ne.-A solution of 4.8 grams of l6-keto-5-androsten-3beta,l7betadiol-S-methyl ether (melting point 192-195 C.) in 500 ml. of methanol was refluxed while a solution of 10 grams of potassium hydroxide in 25 ml. of water were added. While the reflux was continued, two solutions were added simultaneously to the reaction mixture, one solution containing 220 grams of potassium hydroxide in 500 ml. of

Water and the second solution containing 320 ml. of dimethyl sulfate. The simultaneous addition of potassium hydroxide and dimethyl sulfate to the refluxing reaction mixture required 2 /2 hours. After the addition of reagents was completed about 200 ml. of methanol was distilled from the reaction mixture and the residue was cooled and treated with 3 liters of ice water and refrig erated at C. The precipitate of 3beta,17beta-di methoxy-S-androsten-lo-one weighing 2.82 grams was removed by filtration and dried. It melted at 162-168 C. On further recrystallization from methanol with the aid of activated charcoal, large needles of 3beta,17betadimethoxy-S-androsten-16-one melting at 167-169 C. were obtained. The product had a rotation in chloroform 'of [a] =-227.

EXAMPLE 2 1 7beta-meth0xy-16-ket0-5-androsten-3beta-ol. To a refluxing solution of 2.0 grams of 16-keto-5-androsten- 3beta,l7beta-diol (M.P. 206-207 C.) in 200 ml. of methanol were added simultaneously and pro rata 128 ml. of dimethyl sulfate a solution of 88 grams of potassium hydroxide in 200 ml. of water. The addition of potassium hydroxide and dimethyl sulfate required a period of about 2 hours. The reaction mixture was then cooled, diluted with 1800 ml. of ice water and refrigerated at 0 C. The precipitate of l7beta-methoxy-16-keto-5- androsten-Sbeta-ol was removed by filtration, washed with water and dried. 0n recrystallization from aqueous methanol with the aid of activated carbon, the product melted at 169-171" C.

EXAMPLE 2A 17beta-merhoxy-5-androszen-3beta,16beta-diol was produced from 17beta-methoxy-16-keto-5-androsten-3beta-ol by dissolving 700 mg. of the latter in 60 ml. of absolute ethanol and treating the solution at 0 C. with 0.5 gram of sodium borohydride over a period of 3 hours. The mixture was then brought to room temperature for 1 hour after which 700 ml. of cold 0.5% sodium chloride solution and 10 ml. of acetone were added. The reaction mixture was allowed to stand over night in the refrigerator at about 5 C. The precipitate of 17beta-methoxy-5-androsten-3beta, 6beta-diol were removed by filtration and dried. It melted at 188-190 C. On recrystallization from aqueous methanol the product melted at 192-194 C.

EXAMPLE 3 liters of ice water and refrigerated at 0 C. The precipitate of 17beta-methoxyandrostan-Sbeta-ol-l6-one was separated and recrystallized from a mixture of acetone and petroleum ether with the aid of activated carbon followed by recrystallization from aqueous methanol. The 17beta-methoxyandrostan-3beta-ol-16one so obtained melted at 164-165 C.

EXAMPLE 4 I7beta methoxy 16ket0-1,3,5(10)-estratrien-3-ol-3- benzyl ether.-A solution of 1.82 grams of 16-ketoestradiol-3-benzyl ether in 1600 ml. of methanol was mixed with a solution of 6.7 grams of potassium hydroxide in 17 ml. of water. The resulting solution was refluxed and stirred while two solutions were added pro rata simultaneously. One solution contained 88 grams of potassium hydroxide in 250 ml. of water and the second was 127 ml. of dimethyl sulfate. The addition of dimethyl sulfate and potassium hydroxide solution was carried out over a period of 1 /2 hours and refluxing was continued for another 30 minutes. Then 1 liter of ice water was added and the mixture was cooled and refrigerated at 0 C. The precipitate of 17beta-methoxy-3-benzyloxy- 1,3,5 (10)-estratrien-16-one was removed by filtration,

.finally twice with water.

washed with water and dried. There was thus obtained 1.74 grams of product melting at 177-181 C.

1.47 grams of 17beta-methoxy-3-benzyloxy-1,3,5(10)- estratrien-lG-one dissolved in 6 ml. of dry pyridine was treated with 1.5 grams of succinic anhydride. The mixture was heated on a steam bath for 2 hours and then diluted with 23 ml. of water and heated for /2 hour longer. The reaction mixture was cooled and partitioned between 300 ml. of 1 N hydrochloric acid and 750 ml. of ether. The ether solution was washed with 1 N hydrochloric acid, with water and with 0.1 N potassium carbonate solution containing 5% sodium chloride, and The ether solution was then evaporated to dryness and the residue was recrystallized from aqueous methanol with the aid of an activated carbon. There was thus obtained purified 17beta-methoxy- 3-benzyloxy-1,3,5(10)-estratrien-16-one melting at 176 C.

' EXAMPLE 5 1 7 b eta-methoxy-J ,3,5 (10) -estratrien-3-0l-1 6-0ne.-To a solution of 4 grams of 16-ketoestradiol and 2400 ml. of 0.5 N lithium hydroxide solution was added 32 ml. of dimethyl sulfate and the mixture was shaken for 30 minutes at room temperature. Then 28 m1. of additional dimethyl sulfate were added and the shaking continued for 30 minutes longer. Then the mixture was allowed to stand for about 15 hours at room temperature after which it was filtered to remove a precipitate of 16-ketoestradiol dimethyl ether. The filtrate was treated with solid carbon dioxide until the pH was reduced to 7.0-7.5 and then extracted with 2 liters of ether. The ether solution was washed with a liter of 3% sodium bicarbonate solution and with a liter of water. The ethereal solution was then evaporated to dryness on a steam bath and the residue of 16-ketoestradiol-17-methyl ether weighing 720 mg. was dried at 35 C. It was dissolved in 100 ml. of methanol, treated with activated charcoal, filtered and the filtrate evaporated until crystallization occurred. The crystals of 16-ketoestradiol-l7-methyl ether were collected on a filter, washed wih 66% methanol at room temperature. On further recrystallization from 80% aqueous methanol, there was obtained crystals of 16-ketoestradiol-17-methyl ether melting at 271-272 C. (with decomposition).

EXAMPLE 6 3,17beta-dimethoxy-I,3,5(]0)-estratrien 16 one.3 grams of 16-ketoestradiol-3-methyl ether dissolved in 500 ml. of methanol at reflux temperature was treated with a solution of 10 grams of potassium hydroxide and 25 ml. of water. The reaction mixture was agitated and refluxed while a solution of 132 grams of potassium hydroxide in 350 ml. of water was added simultaneously with ml. of dimethyl sulfate over a period of 2.5 hours. The reaction mixture was cooled to room temperature and diluted with 4.5 liters of ice water. On standing over night a precipitate of 16-ketoestradiol-3,l7-dimethyl ether formed. Upon recrystallization from 70% methanol, 3. yield of 1.85 grams of this product melting at 197 .5-200 C. was obtained.

What is claimed as new and is desired to be secured by Letters Patent of the United States is:

1. A method of producing a 17beta-lower-alkoxy-16- ketocyclopentanopolyhydrophenanthrene which comprises reacting a 17beta-hydroxy-16-ketocyclopentanopolyhydrophenanthrene with an excess of a dilower-alkyl sulfate simultaneously with the pro rata addition of a stoichiometric equivalent amount of caustic alkali solution.

2. A method of producing a 17beta-lower-alkoxy-16- ketocyclopentanopolyhydrophenanthrene which comprises reacting a 17beta-hydroxy-16-ketocyclopentanopolyhydrophenanthrene at a temperature in the range of 50-150 C. with an excess of a di-lower-alkyl sulfate simultaneously with the pro rata addition of a stoichiometric equivalent amount of caustic alkali solution over a period of A to 4 hours.

5 3. The method of claim 2 wherein the di'lowepalkyl 7. The method of claim 3 wherein the l7beta-hydroxysulfate is dimethyl sulfate. 16-ketocyclopentanopolyhydrophenanthrene is 16 keto- 4. The method of claim 3 wherein the 17beta-hydroxyestradiol. 16-ketocyclopentanopolyhydrophenanthrene is 16-ket0-5- 8. The method of claim 3 wherein the 17beta-hydroxyandrosten-3beta,17beta-dio1-3-methyl ether. 5 16-ketocyclopentanopo1yhydrophenanthrene is 16 keto- 5. The method of claim 3 wherein the 17beta-hydroxyestradiol-3-benzyl ether. 16-ketocyclopentanopolyhydrophenanthrene is 16-keto-5- andmstensbeta,l7beta'diol- References Cited in the file of this patent 6. The method of claim 3 wherein the l7beta-hydroxyl6-ket0cycl0pentanopolyhydrophenanthrene is 16 keto- 10 UNITED STATES PATENTS androsten-Bbeta,17beta-diol. 2,949,476 Tyner Aug. 16, 1960 UNITED STATES. PATENT OFFICE CERTIFICATE, OF CORRECTION Patent No. 3,067,215 December 4,, 1962 Max N, Huffman It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 5 line 11 for "androstenread androstan== =8 Signed and sealed thisv 14th day of May 1963.,

( SEAL) Attest:

ERNEST w. SWIDER DAVID LADD Attesting Officer Commissioner of Patents i 

1. A METHOD OF PRODUCING A 17BETA-LOWER-ALKOXY-16KETOCYCLOPENTANOPOLYHYDROPHENANTHRENE WHICH COMPRISES REACTING A 17BETA-HYDROXY-16-KETROCYCLOPENTANOPOLYHYDROPHENANTHRENE WITH AN EXCESS OF A DI-LOWER-ALKYL SULFATE SIMULTANEOUSLY WITH THE PRO RATA ADDITION OF A STOICHIOMETRIC EQUIVALENT AMOUNT OF CAUSTIC ALKALI SOLUTION. 